Introduction: CARTITUDE-4 is a phase 3 randomized controlled trial (RCT) assessing the efficacy and safety of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in patients with relapsed and refractory multiple myeloma (RRMM) who have received one to three prior line(s) of therapy that included an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI), and who are refractory to lenalidomide. CARTITUDE-4 demonstrated superiority of cilta-cel over PVd and DPd on progression-free survival (PFS) and response rates (overall response rate [ORR], very good partial response [VGPR] or better, and complete response [CR] or better [CR or stringent CR]). Other available therapies for the treatment of this patient population where individual patient data was available for analysis include: daratumumab in combination with bortezomib and dexamethasone (DVd), bortezomib in combination with dexamethasone (Vd), carfilzomib in combination with daratumumab and dexamethasone (DKd) or dexamethasone alone (Kd), and pomalidomide in combination with dexamethasone (Pd). This analysis aims to compare efficacy outcomes in patients randomized to the cilta-cel arm (i.e., patients apheresed or infused with cilta-cel) in CARTITUDE-4 vs each of these regimens in the same target population. Methods: Individual patient data were collected from the CARTITUDE-4 (cilta-cel), CASTOR (DVd and Vd), CANDOR (DKd and Kd), and APOLLO (Pd) RCTs. Patients who met CARTITUDE-4 eligibility criteria were identified from the above mentioned RCTs. As no patients in the comparative trials had prior treatment with anti-CD38, patients with prior exposure to anti-CD38 therapies in the cilta-cel cohort were excluded. Key prognostic baseline covariates including refractory status, ISS stage, presence of extramedullary disease, and time to progression on prior line, were adjusted for using inverse probability of treatment weighting (IPTW), with average treatment effect in the treated weights. Differences in baseline characteristics were assessed using standardized mean differences. PFS, ORR, VGPR or better, and CR or better were compared between patients in the cilta-cel arm and the comparator regimens. Relative efficacy of cilta-cel vs comparator regimens were estimated with hazard ratios (HRs) and 95% confidence intervals (CIs) from weighted Cox proportional hazards models for PFS, and response rate ratios (RRs) and 95% CIs from weighted logistic regression models for ORR, VGPR or better, and CR or better. Sensitivity analyses using alternative statistical approaches and including additional covariates were explored. Results: After the exclusion of 53 patients with prior exposure to an anti-CD38 therapy, 155 patients in the cilta-cel arm remained. Across the comparative trials, 44 patients treated with DVd, 46 patients treated with Vd, 98 patients treated with DKd, 46 patients treated with Kd, and 92 patients treated with Pd met the inclusion criteria of CARTITUDE-4. Baseline covariates were similar across the cohorts after IPTW. Patients randomized to the cilta-cel arm showed significant improvements in PFS (adjusted HRs from 0.11 vs Vd to 0.51 vs DKd), VGPR or better (adjusted RRs from 1.51 vs DKd to 5.13 vs Vd), and CR or better rate (adjusted RRs from 2.90 vs DKd to 35.24 vs Pd) (Table). Improvements in ORR were also observed against all comparator regimens (adjusted RRs from 1.22 vs DKd to 1.90 vs Pd), though were marginally not statistically significant vs DVd and Kd. Treatment with DKd consistently yielded the best results out of all comparator regimens, but results were still in favor of cilta-cel. Results of cilta-cel benefit were consistent across sensitivity analyses, yielding adjusted HRs below 1.00 and RRs above 1.00 in all cases against other comparator regimens. Conclusions: Data from CARTITUDE-4 and these analyses demonstrate the benefit of cilta-cel over additional regimens commonly used in clinical practice, highlighting its potential to become a new standard of care option for patients with RRMM, who have received one to three prior lines(s) of therapy, including an IMiD and a PI, and who are refractory to lenalidomide. These comparisons provide valuable information to contextualize the efficacy of CARVYKTI in countries where standard of care may be different from DPd/PVd.

Introduction: Ciltacabtagene autoleucel (cilta-cel; Carvykti) was assessed in the phase 3 randomized controlled trial CARTITUDE-4 for adult patients with relapsed and refractory multiple myeloma (RRMM) who have received 1-3 prior line(s) of therapy (LOT) that included an immunomodulatory agent (IMiD), and a proteasome inhibitor (PI) and are refractory to lenalidomide. Other therapies used to treat patients with multiple myeloma who have received at least one other therapy and are lenalidomide-refractory vary by country, but broadly include doublet and triplet regimens based on daratumumab, pomalidomide, bortezomib, and carfilzomib. This analysis aims to compare efficacy outcomes in patients randomized to the cilta-cel arm of CARTITUDE-4 versus relevant comparators based on their target trial populations. Methods: Comparators for the matching adjusted indirect comparisons (MAICs) were identified a priori based on regimens used in the target population including; SVd, EloPd, IsaKd, DKd, DVd, Kd, Vd, Pd, and Ide-cel. PVd and DPd were not of interest given their inclusion in the CARTITUDE-4 trial. Melflufen+d, PanVd, VenVd, PCd, IxaKd, D-monotherapy, V-monotherapy, CyVd, and DVCd were not of interest for the US, EU-5, the Netherlands, and Canada. A systematic literature review identified publications of relevant clinical trials for these treatments, which were assessed for feasibility of an indirect treatment comparison. Feasibility was determined based on study design and degree of overlap with the CARTITUDE-4 population (prior LOT, lenalidomide-refractoriness, and exclusion criteria around previous therapies, i.e., prior daratumumab). We report here on comparisons vs. EloPd (ELOQUENT-3), IsaPd (ICARIA-MM), and SVd (BOSTON). Due to differences in methods for the comparisons versus ide-cel (KarMMa-3) and versus DKd, Kd, DVd, Vd, and Pd, these are reported separately. Comparison to IsaKd was not feasible due to a lack of published data in the lenalidomide-refractory subgroup (baseline characteristics and efficacy data), and key differences in exclusion criteria. Given the lack of a common comparator between CARTITUDE-4 and the comparator trials, unanchored MAICs were performed utilizing individual patient-level data (IPD) from patients randomized to the cilta-cel arm of CARTITUDE-4 (N=208). The eligibility criteria from each of the comparator trials were applied to the cilta-cel IPD, and outcomes for the matched population were compared against published summary data for EloPd (N=60), IsaPd (N=154), and SVd (N=195) using reconstructed IPD for response endpoints and simulated IPD from published Kaplan-Meier (KM) curves for progression-free survival (PFS). Further imbalances in patient characteristics were adjusted by weighting the cilta-cel data to match the reported baseline characteristics of the comparator trials in terms of refractory status, cytogenetic risk, ISS stage, and presence of extramedullary disease. Comparative efficacy was estimated for overall response rate (ORR), very good partial response or better (≥VGPR) rate, complete response or better (≥CR) rate, and PFS. For binary endpoints, relative effects were quantified using relative response ratios (RRs) with 95% confidence intervals (CIs) derived from a weighted logistic regression analysis. For PFS, HRs including 95% CIs were estimated using a weighted Cox proportional hazards model. Results: After adjustment, patients in the cilta-cel arm were significantly more likely to achieve an overall response than patients in EloPd or IsaPd arms, and to achieve ≥VGPR and ≥CR versus patients in all other comparators arms ( Table 1). In addition, cilta-cel was associated with a significant reduction in the risk of disease progression or death (PFS) versus all comparators, ranging from 39% (versus SVd) to 68% (versus IsaPd) ( Table 2). Conclusions: Cilta-cel demonstrated clinical benefit over EloPd, IsaPd, and SVd for response outcomes and PFS, highlighting its potential as an effective treatment option for patients with RRMM who have received at least one other therapy and are lenalidomide-refractory. These comparisons provide valuable information to contextualize the efficacy of cilta-cel in countries where treatment for these patients may be different from DPd or PVd.

Introduction: Two novel B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T-cell (CAR-T) therapies, ciltacabtagene autoleucel (cilta-cel; Carvykti) and idecabtagene vicleucel (ide-cel; Abecma), were recently developed and approved in 2022 and 2021, respectively, for heavily pre-treated relapsed/refractory multiple myeloma (RRMM) based on the CARTITUDE-1 and KarMMa studies. A previous comparison of these therapies in triple-class exposed patients demonstrated improved efficacy with cilta-cel versus ide-cel (Martin T, et al. Curr Med Res Opin. 2023;39(1):81-89). More recently, the efficacy and safety of these CAR-Ts were demonstrated earlier in the treatment pathway in lenalidomide-refractory, proteasome inhibitor (PI)-exposed patients with 1-3 prior line(s) of treatment (LOT; cilta-cel; CARTITUDE-4), and in triple-class exposed patients with 2-4 prior LOT (ide-cel; KarMMa-3). In the absence of a head-to-head comparison of these two therapies, an unanchored matching-adjusted indirect comparison (MAIC) was used to estimate their relative efficacy using data from CARTITUDE-4, CARTITUDE-1, and KarMMa-3. Methods: While KarMMa-3 and CARTITUDE-4 both included DPd in the physician's choice control arm, there is no published data on this subgroup from KarMMa-3. As such, an unanchored MAIC was performed utilizing individual patient-level data (IPD) from 245 patients who received cilta-cel; 208 patients from CARTITUDE-4 who had received 1-3 prior LOT and 37 patients from CARTITUDE-1 who had received 3-4 prior LOT. From these data, cilta-cel patients who fulfilled the inclusion criteria from KarMMa-3 (2-4 prior LOT and triple-class exposed) were selected, and their outcomes were compared against published summary data for ide-cel (N=254) from KarMMa-3 using reconstructed IPD for response endpoints and simulated IPD from published Kaplan-Meier (KM) curves for progression-free survival (PFS). Further imbalances in patient characteristics were adjusted for by weighting the cilta-cel IPD to match the reported baseline characteristics of KarMMa-3 in terms of refractory status, ISS stage, time to progression on prior LOT, cytogenetic risk, and presence of extramedullary disease. Comparative efficacy was estimated for overall response rate (ORR), very good partial response or better (≥VGPR) rate, complete response or better (≥CR) rate, and PFS. For binary endpoints, relative effects were quantified using relative response ratios (RRs) with 95% confidence intervals (CIs) derived from a weighted logistic regression analysis. For PFS, the hazard ratio (HR) with 95% CIs for cilta-cel versus ide-cel was estimated using a weighted Cox proportional hazards model. Results: After applying the KarMMa-3 inclusion and exclusion criteria to the CARTITUDE-1 and CARTITUDE-4 IPD (excluding patients with only 1 prior LOT or no prior daratumumab), 36 patients and 49 patients were included from the cilta-cel trials, respectively. After adjustment, patients in the cilta-cel group (effective sample size [ESS]=46) were significantly more likely to achieve an overall response (RR: 1.18 [95% CI: 1.04, 1.33]; p=0.0404), and to reach deeper levels of response as demonstrated by ≥VGPR (RR: 1.34 [95% CI: 1.16, 1.56]; p=0.0027), and ≥CR (RR: 1.91 [95% CI: 1.56, 2.34]; p<0.0001) compared to patients in the ide-cel group ( Table). In addition, a statistically significant reduction of 49% in the risk of disease progression or death was observed with cilta-cel versus ide-cel (HR: 0.51 [95% CI: 0.31, 0.84]; p=0.0078; Figure). Conclusions: This unanchored MAIC showed that cilta-cel provides clinical benefit over ide-cel across response outcomes and PFS for patients with triple-class exposed RRMM treated with 2-4 prior LOT. These results are consistent with the previous comparison in later line, triple-class exposed patients, continuing to highlight the value of cilta-cel for these patients. Furthermore, these comparisons provide valuable information to contextualize the efficacy of cilta-cel compared to other available CAR-Ts for multiple myeloma.